Coronary heart disease (CHD) is the leading cause of death in both the U.S and Mexico. Unfavorable serum lipid levels, such as high serum total cholesterol, high serum triglycerides and low high-density lipoprotein cholesterol, are well-known risk factors for CHD. Although several studies have demonstrated that the Mexican population has an increased predisposition to dyslipidemias, this population is underinvestigated for the genetic factors conferring this susceptibility. Considering the rapid growth of the Mexican-American population in the U.S., investigation of these genetic factors in the Mexican population is of great importance and relevant also to this U.S. minority. To identify genetic variants that confer susceptibility to high serum lipid levels in Mexicans, we recently began an international collaboration between investigators at UCLA, Los Angeles, and Institute Nacional de Ciencias Medicas y Nutricion, Mexico City. We examined 24 extended Mexican familial combined hyperlipidemia (FCHL) families for one gene and seven chromosomal loci previously detected for FCHL in Caucasian families. FCHL is the most common mixed dyslipidemia predisposing to CHD, with an estimated prevalence of 8% in Mexicans. We demonstrated that the upstream transcription factor 1 (USF1) gene and chromosomal loci on 10q and 16q are implicated in the Mexican FCHL families (Huertas-Vazquez et al. 2005). This study is the first one to extensively investigate the genetic component of the FCHL disorder in Mexicans. Recently, we also identified significant associations between DMA variants in the hepatic nuclear factor 4, alpha (HNF4A) gene and FCHL in Mexicans. Although HNF4A variants have previously been associated with type 2 diabetes mellitus (T2DM), our data show for the first time that the HNF4A variants are associated with serum lipid levels. Considering the clear phenotypic overlap between T2DM and FCHL, we hypothesize that HNF4A is a good candidate gene for FCHL as weJI. We propose to identify novel susceptibility loci for common lipid disorders in Mexicans and further examine these implicated genes. In Specific Aim 1, we will perform a genome scan in Mexican FCHL families to identify additional susceptibility loci undiscovered or nonexistent in the previously studied Caucasian populations. In Specific Aim 2, we will investigate USF1, HNF4A and the chromosomal loci implicated in the genome scan to characterize the DNA variants conferring the susceptibility to FCHL in Mexicans.